Crystalline cefdinir salts

ABSTRACT

Cefdinir crystalline salts of formula (I), in which n ranges from 1 to 3, the preparation and use thereof for the preparation and purification of cefdinir is herein disclosed. The salts of formula (I) can be obtained from cefdinir intermediates or crude cefdinir by treatement with phosphoric acid.

FIELD OF THE INVENTION

The present invention relates to crystalline cefdinir salts and to theprocess for the preparation thereof. These salts are usefulintermediates in the synthesis and purification of cefdinir.

BACKGROUND OF THE INVENTION

whose chemical name is[(−)-(6R,7R)]-7-{[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido}-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0] oct-2-en-2-carboxylic acid, is a third generation semisyntheticcephalosporin for the oral use, characterized by a broad antibacterialactivity spectrum and by antibiotic activity against gram-positive andgram-negative bacteria higher than that of other antibiotics for theoral administration. In particular, cefdinir shows an excellentantibacterial activity against staphylococci and streptococci.

Cefdinir is usually prepared through processes which envisage theprotection of one or more of the primary amino, hydroxyimino or carboxyfunctions. The protective groups are removed at the end of the synthesisby means of acid hydrolysis.

U.S. Pat. No. 4,559,334 discloses a method for the preparation ofcefdinir benzhydryl ester, which is hydrolysed with TFA in anisole orwith BF3Et₂O.

WO 01/79211 teaches to prepare cefdinir via protection of thehydroxyimino and carboxy functions with a benzhydryl and ap-methoxybenzyl group respectively, which are subsequently removed withperchloric acid in an aprotic solvent and in the presence of an organicacid.

WO 97/24358 dicloses the preparation of a cefdinir salt withp-toluenesulfonic acid wherein the hydroxyimino function is protectedwith a trityl group.

Since cefdinir is poorly stable to acids, the aforementioned methodsgive sometimes unsatisfactory yields and the purity does not comply withthe pharmacopoeia standards. The resulting product must therefore besubjected to further purification, for example to recrystallization(according to U.S. Pat. No. 4,935,507) or to formation of salts(according to U.S. Pat. No. 6,350,869).

DETAILED DISCLOSURE OF THE INVENTION

It has now been found that cefdinir salts of formula (I)

wherein n ranges from 1 to 3,

as well as hydrates and solvates thereof, allow to overcome theaforementioned drawbacks and are particularly useful intermediates inthe preparation and purification of cefdinir.

Particularly preferred is the salt of formula (I) in which n is 2.

The salts of formula (I) are obtained by treating with phosphoric acidcefdinir protected forms of formula (III)

wherein

R₁ is a benzhydryl, trityl or p-methoxybenzyl group, and

R₂ is benzhydryl, t-butyl or p-methoxybenzyl group.

The reaction is carried out in a protic or aprotic, polar or apolarorganic solvent, or in a mixture thereof. In more detail, the solvent isselected from nitrites, preferably acetonitrile or propionitrile;esters, preferably ethyl acetate, butyl acetate, ethyl formate andmethyl acetate; amides, preferably N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP); ketones,preferably acetone and methyl ethyl ketone; ethers, preferablytetrahydrofuran (THF) or dioxane; sulfoxides or sulfones, preferablydimethylsulfoxide (DMSO) and sulfolane; carboxylic acids, preferablyformic and acetic acid; chlorinated solvents, preferably methylenechloride; and alcohols, preferably methanol, ethanol and isopropanol.

According to a particularly preferred embodiment of the invention, thesolvent is acetonitrile.

Phosphoric acid is added, in the solid form or as an aqueous solution,in amounts ranging from 1 to 20 equivalents, preferably from 1 to 10equivalents.

The reaction temperature ranges from −10° C. to 60° C., more preferablyfrom 0° C. to 45° C.

The salts (I) usually crystallize in the reaction mixture and arerecovered by filtration. To achieve complete precipitation, an organicsolvent selected from the following can be added: nitriles, preferablyacetonitrile or propionitrile; esters, preferably ethyl acetate, butylacetate, ethyl formate and methyl acetate; ketones, preferably acetoneand methyl ethyl ketone; ethers, preferably diethyl ether, diisopropylether and tert-butylmethyl ether.

The preparation of the salts (I) allows to simultaneously hydrolyse theprotective groups and obtain cefdinir intermediates which are easilyrecoverable in the crystalline form, stable and highly pure (the purityis generally higher than 98%).

The salts (I) can be easily converted to cefdinir, or to a hydrated orsolvated form thereof, by means of conventional methods, for example bytreatment with an organic base, preferably a tertiary amine, morepreferably triethylamine, or with an inorganic base, preferably ammonia,or carbonates, bicarbonates, hydroxides or phosphates of alkalinemetals, preferably sodium or potassium, and optional treatment of theresulting salts with conventional acids. The reaction solvent can bewater, or a mixture of water and alcohols, preferably methanol, ethanol,propanol or butanol; ketones, preferably acetone or methyl ethyl ketone,tetrahydrofuran or acetonitrile. The resulting solutions are treatedwith conventional acids; usually cefdinir precipitates as the solvate.

The salts of formula (I) are moreover particularly useful for thepurification of crude cefdinir obtained by any other synthetic method.For this purpose, crude cefdinir is dissolved in water or in a protic oraprotic, polar organic solvent, or mixtures thereof, by addition ofphosphoric acid, in the solid form or as an aqueous solution, in amountsranging from 1 to 20 equivalents, preferably from 1 to 10 equivalents,at a temperature ranging from −10° C. to 60° C., preferably from 0 to30° C. The organic solvent is selected from nitrites, preferablyacetonitrile and propionitrile; amides, preferably N,N-dimethylformamide(DMF), N,N-dimethylacetamide (DMA) and N-methylpyrrolidone (NMP);ketones, preferably acetone; ethers, preferably tetrahydrofuran (THF);alcohols, preferably methyl, ethyl, propyl, isopropyl or n-butylalcohol.

Usually, the salts (I) spontaneously crystallize from the reactionmixture, but crystallization can also be triggered and completed byaddition of an organic solvent selected from those previously indicatedfor this purpose.

Once precipitation is complete, the salts (I) are recovered andconverted to cefdinir as described above.

The invention is now illustrated by means of the following examples.

EXAMPLES Example 17-(Z)-[2-(2-Aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid phosphate

100 Grams of7-(Z)-[2-(2-aminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid dicyclohexylamine salt was dissolved in a solution of 67 ml of 85%phosphoric acid in 1000 ml of acetonitrile. The mixture was heated at45° C. for 2 hours, until complete conversion of the starting product(HPLC). After cooling to 20° C., the precipitate was filtered and washedwith acetonitrile. After drying, 61 grams of cefdinir phosphate wasobtained.

HPLC purity=98% (according to the method of the XIV Japanesepharmacopoeia)

¹H-NMR analysis confirmed the structure of the product, while ³¹P-NMRanalysis confirmed the presence of phosphoric acid, which was alsoevident from the IR spectrum, showing characteristic bands at about 1115and 970 cm⁻¹.

¹H-NMR (DMSO-d₆, 300 MHz): 11.27 (1H, broad s), 9.47 (2H, d, J=8.3 Hz),7.13 (2H, broad s), 6.93 (1H, dd, J=17.5 Hz and 11.5 Hz), 6.68 (1H, s),5.80 (1H, dd, J=8.3 Hz and 5 Hz), 5.60 (1H, d, J=17.5 Hz), 5.33 (1H, d,J=11.5 Hz), 5.20 (1H, d, J=5 Hz); 3.80 and 3.57 (2H, AB system, J=17.9Hz).

Example 27-(Z)-[2-(2-Aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid phosphate

80 Grams of7-(Z)-[2-(2-aminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid was dissolved in a solution of 60 ml of 85% phosphoric acid in 1000ml of acetonitrile. The mixture was heated at 45° C. for 2 hours untilcomplete conversion of the starting product (HPLC). After cooling to 20°C., the product was filtered, washed with acetonitrile and dried. 61Grams of cefdinir phosphate was obtained.

Example 37-(Z)-[2-(2-Aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid phosphate

10 Grams of7-(Z)-[2-(2-aminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid benzhydryl ester (prepared as reported in preparation A) is addedto a solution of 21 ml of 85% phosphoric acid in 106 ml of acetonitrile.The mixture was heated at 45° C. for 6 hours, until complete conversionof the starting product (HPLC). After cooling to 20° C., the precipitatewas filtered, washed with acetonitrile and dried. 2.8 Grams of cefdinirphosphate was obtained.

HPLC purity=99% (according to the method of the XIV Japanesepharmacopoeia).

Example 47-(Z)-[2-(2-Aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid phosphate

10 Grams of crude cefdinir (94% HPLC purity) (prepared according to WO98/45299) was dissolved in 15 ml of 85% phosphoric acid and 15 ml ofacetonitrile. The resulting solution was heated to 30° C. and cefdinirphosphate was crystallized by addition of 230 ml of acetonitrile. Aftercooling to 20° C., the precipitate was filtered, washed withacetonitrile and dried. 14 Grams of cefdinir phosphate was obtained.

HPLC purity˜99% (according to the method of the XIV Japanesepharmacopoeia).

Example 57-(Z)-[2-(2-Aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (cefdinir)

10 Grams of cefdinir phosphate was dissolved in 200 ml of water,adjusting the pH to 6 by addition of diluted ammonia at 5° C. and thesolution was treated with active charcoal. After removal of thecharcoal, the pH was adjusted to 2.5 by addition of diluted hydrochloricacid at 35° C. After 15 minutes the solution was cooled to 5° C. and thecrystallized product was filtered, washed with water and dried. 6 Gramsof cefdinir was obtained.

HPLC purity=99.5% (according to the method of the XIV Japanesepharmacopoeia)

T_((1%, 510 nm))=99.0% (test reported in U.S. Pat. No. 4,935,507)

Preparation A

7-(Z)-[2-(2-Aminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid benzhydryl ester

A suspension of 75 grains of 7-amino-3-vinyl-3-cephem-4-carboxylatebenzhydryl hydrochloride in methylene chloride is treated under stirringwith bis-trimethylsilylacetamide (90 ml) to obtain a clear solution. 60Grams of 2-(Z)-(2-aminothiazol-4-yl)-2-trityloxyiminoacetic acidS-mercaptobenzothiazolyl ester is added and stirring is continued untilcompletion of the reaction. The reaction mixture is poured in water (1litre) and the phases are separated. The organic phase is dried oversodium sulfate and concentrated under vacuum. The residue is taken upwith methylene chloride and methanol (1:1) under stirring. The solid isfiltered and dried under vacuum to obtain about 105 g of product.

¹H-NMR (CDCl₃, 300 MHz): 7.2-7.5 (26H, m), 7.05 (1H, dd, J=17.6 Hz and11.3 Hz), 6.99 (1H, s), 6.74 (1H, d, J=8.5 Hz), 6.67 (2H), 5.95 (1H, dd,J=8.5 Hz e 5.0 Hz), 5.44 (1H, d, J=17.9 Hz), 5.30 (1H, d, J=11.6 Hz),5.07 (1H, d, J=5.0 Hz), 3.41 e 3.42 (2H, AB system, J_(AB)=17.6 Hz).

1. Cefdinir salts of formula (I)

wherein n ranges from 1 to 3, the hydrates and solvates thereof. 2.Cefdinir salt as claimed in claim 1 wherein n is
 2. 3. Cefdinir saltsaccording to claim 1 in the crystalline form.
 4. A process for thepreparation of salts of formula (I) comprising the treatment withphosphoric acid of a compound of formula (III)

wherein R₁ is a benzhydryl, trityl or p-methoxybenzyl group, and R₂ isbenzhydryl, t-butyl or p-methoxybenzyl group.
 5. A process as claimed inclaim 4 characterized in that use is made of an organic solvent selectedfrom: acetonitrile, propionitrile, ethyl acetate, butyl acetate, ethylformate, methyl acetate, N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), acetone, methylethyl ketone, tetrahydrofuran (THF), dioxane, dimethylsulfoxide (DMSO),sulfolane, formic acid, acetic acid, methylene chloride, methanol,ethanol and isopropanol.
 6. A process as claimed in claim 5characterized in that the solvent is acetonitrile.
 7. A processaccording to claim 4 characterized in that use is made of 1 to 20equivalents of phosphoric acid.
 8. A process for the preparation ofcefdinir (II)

comprising the treatment of salts of formula (I) with an organic orinorganic base, in which the organic base is triethylainine and theinorganic base is selected from ammonia, sodium carbonate orbicarbonate, potassium hydroxide or sodium or potassium phosphate,followed by treatment of the resulting solution with conventional acids.9. A process according to claim 8 wherein the salt of formula (I) isobtained by reacting crude cefdinir with phosphoric acid.